Process for producing guanidine derivatives, intermediates therefor and their production

ABSTRACT

A process for producing the compound [I] or a salt thereof having excellent pesticidal activity as shown in the following schema. ##STR1##

This application is a §371 national phase of PCT/JP96/01694, filed Jun.19, 1996.

TECHNICAL FIELD

The present invention relates to a process for producing guanidinederivatives which are useful as insecticides, novel intermediatestherefor, and a process for producing the intermediates.

BACKGROUND ART

EP-A 376279 corresponding to JP-A H3(1991)-157308, for instance,describes guanidine derivatives having pesticidal activity and a processfor producing the derivatives. Moreover, as an improved productionprocess for the guanidine derivatives, EP-A 452782 corresponding to JP-AH5(1993)-9173 discloses a production process via an isothioureaderivative having a cyclic diacyl group as shown in the followingschema 1. ##STR2## wherein R₁, R₂, R_(4a), and R_(5a) are the same ordifferent, H or a hydrocarbon group which may optionally be substituted;A' is a divalent hydrocarbon group which may optionally be substituted;Q' is a heterocyclic group which may optionally be substituted; X' is anelectron withdrawing group; Y₁ and Y₂ are the same or different, aleaving group; n is 0 or 1.

Furthermore, EP-A 375907 corresponding to JP-A H2(1990)-288860 disclosesguanidine derivatives having pesticidal activity, and the followingprocess for producing the derivatives. ##STR3## wherein R^(1') andR^(2') are hydrogen or C₁₋₄ alkyl, R^(4') is C₁₋₄ alkyl, Z is a five- orsix-membered heterocyclic group having at least one nitrogen atom whichmay be substituted by halegen or C₁₋₄ alkyl, R^(5') and R^(6') arehydrogen or C₁₋₄ alkyl.

However, in these processes for producing the guanidine derivatives,there are some problems such that a mercaptan compound of RSH (wherein Ris a hydrocarbon group which may optionally be substituted) having badsmell is formed as a by-product.

In the above state of the art, the object of present invention is toprovide a process which is advantageous to an industrial mass productionof guanidine derivatives in a higher yield by simple and convenientreaction procedures without bad smell, novel intermediates therefor, anda process for producing the intermediates.

DISCLOSURE OF INVENTION

To accomplish the above-mentioned object, the inventors of the presentinvention earnestly explored for a new production route to a guanidinederivative of the formula [I]: ##STR4## wherein R² is H or a hydrocarbongroup which may optionally be substituted; R³ is an amino group whichmay optionally be substituted; Q is a heterocyclic group which mayoptionally be substituted; X is an electron attracting group; n is 0 or1.

As a result, the inventors discovered that anN-cyclodiacyl-N'-substituted isourea derivative of the formula [IV]:##STR5## wherein R¹ is a hydrocarbon group which may optionally besubstituted, A is a divalent hydrocarbon group which may optionally besubstituted, and X is as defined above, can be produced in high yield byreacting an N-substituted isourea derivative of the formula [II]:##STR6## wherein the symbols are as defined above, or a salt thereof,with a compound of the formula [III]: ##STR7## wherein Y¹ and Y² are thesame or different, a leaving group; A is as defined above.

The inventors further found that a compound of the formula [VI]:##STR8## wherein the symbols are as defined above, or a salt thereof,can be produced in high yield by reacting the compound [IV] with acompound of the formula [V]:

    Q--(CH.sub.2).sub.n --NH--R.sup.2                          [V]

wherein the symbols are as defined above, or a salt thereof.

Based on the above findings, the inventors did further research andfound surprisingly that when the compound [VI] or a salt thereof isreacted with an amine or a salt thereof either in water or in a mixtureof water and an organic solvent, the guanidine derivative [I] or a saltthereof is produced in high yield.

And, the inventors further found that the compound [VI] or a saltthereof can be produced by reacting the compound [II] or a salt thereofwith the compound [V] or a salt thereof not via the compound [IV]. Theinventors did further reseach and discovered to their own surprise thatthe compound [VI] or a salt thereof can be produced in a furtherimproved yield by conducting the above reaction in the presence of anacid either in water or in a mixture of water and an organic solvent.

Based on these findings, the inventors have conducted further study toaccomplish the present invention.

The present invention, therefore, is directed to:

(1) a process for producing a compound of the formula [VI]: ##STR9##wherein R¹ is a hydrocarbon group which may optionally be substituted,R² is H or a hydrocarbon group which may optionally be substituted, Q isa heterocyclic group which may optionally be substituted, X is anelectron attracting group, and n is 0 or 1, or a salt thereof, whichcomprises

(A) reacting a compound of the formula [II]: ##STR10## wherein thesymbols are as defined above, or a salt thereof, with a compound of theformula [V]:

    Q--(CH.sub.2).sub.n --NH--R.sup.2                          [V]

wherein the symbols are as defined above, or a salt thereof, or

(B) reacting the compound [II] or a salt thereof with a compound of theformula [III]: ##STR11## wherein A is a divalent hydrocarbon group whichmay optionally be substituted, and Y¹ and Y² are the same or different,a leaving group, and further reacting the resultant compound of theformula [IV]: ##STR12## wherein the symbols are as defined above, withthe compound [V] or a salt thereof,

(2) a process according to (1), wherein R¹ is a C₁₋₃ alkyl group,

(3) a process according to (1), wherein X is nitro,

(4) a process according to (1), wherein R² is H or a C₁₋₄ alkyl group,

(5) a process according to (1), wherein Q is a 5- or 6-membered aromaticheterocyclic group, having at least one nitrogen atom or sulfur atom,which may optionally be halogenated,

(6) a process according to (1), wherein n is 1,

(7) a process according to (1), wherein the reaction in process (A) isconducted in water or in a mixture of water and an organic solvent,

(8) a process according to (1), wherein the reaction in process (A) isconducted in the range of about pH 5 to pH 8,

(9) a process for producing a compound of the formula: ##STR13## whereinR³ is an amino group which may optionally be substituted, and R², Q, Xand n are as defined above, or a salt thereof, which comprises

(i) (A) reacting the compound of the formula [II] or a salt thereof,with the compound of the formula [V] or a salt thereof, or (B) reactingthe compound of the formula [II] or a salt thereof, with the compound ofthe formula [III], and further reacting the resultant compound of theformula [IV], with the compound of the formula [V] or a salt thereof,and further

(ii) reacting the resultant compound of the formula [VI] or a saltthereof, with an amine compound or a salt thereof,

(10) a process for producingO-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea or a salt thereof,which comprises reacting O-methyl-N-nitroisourea or a salt thereof with5-(aminomethyl)-2-chloropyridine or a salt thereof,

(11) a process for producingO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea or a saltthereof, which comprises reacting O-methyl-N-nitroisourea or a saltthereof with 5-(aminomethyl)-2-chlorothiazole or a salt thereof,

(12) the compound of the formula [IV],

(13) a compound according to (12), wherein R¹ is a C₁₋₃ alkyl group,

(14) a compound according to (12), wherein A is a C₆₋₁₄ arylene group,

(15) a compound according to (12), wherein X is nitro,

(16) a compound according to (12), which isO-methyl-N-nitro-N'-phthaloylisourea,

(17) a process for producing the compound [IV], which comprises reactingthe compound [II] or a salt thereof, with the compound [III],

(18) a process for producing the compound [VI] or a salt thereof, whichcomprises reacting the compound [IV], with the compound [V] or a saltthereof,

(19) a process according to (9), wherein the reaction is conducted inwater or in a mixture of water and an organic solvent,

(20) a process according to (9), wherein the amine compound isrepresented by the formula:

    R.sup.4 R.sup.5 NH

wherein R⁴ and R⁵ are the same or different, H or a hydrocarbon groupwhich may optionally be substituted, or both R⁴ and R⁵ are combined withthe adjacent nitrogen atom to form a cyclic amino group,

(21) a process according to (9), wherein the amine compound is a C₁₋₄alkylamine,

(22) a process for producing1-(6-chloro-3-pyridylmethyl)-3-methyl-2-nitroguanidine or a saltthereof, which comprises reactingO-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea or a salt thereof,with methylamine or a salt thereof in water or in a mixture of water andan organic solvent, and

(23) a process for producing1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine or a saltthereof, which comprises reactingO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea or a saltthereof, with methylamine or a salt thereof in water or in a mixture ofwater and an organic solvent.

The hydrocarbon group of the hydrocarbon group which may optionally besubstituted for R¹ and R² includes saturated and unsaturated aliphatichydrocarbon groups and aromatic hydrocarbon groups. The preferredsaturated or unsaturated aliphatic hydrocarbon groups are C₁₋₁₅ alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, tridecyl, tetradecyl and pentadecyl, C₂₋₁₀ alkenyl groups suchas vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl and 3-octenyl,C₂₋₁₀ alkynyl groups such as ethynyl, 2-propynyl and 3-hexynyl, C₃₋₁₀cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl, and C₃₋₁₀ cycloalkenyl groups such as cyclopropenyl,cyclopentenyl and cyclohexenyl. The preferred aromatic hydrocarbongroups are C₆₋₁₄ aryl groups such as phenyl, naphthyl, azulenyl, anthryland phenanthryl, and C₇₋₁₁ aralkyl groups such as benzyl andphenylethyl.

The heterocyclic group of the heterocyclic group which may optionally besubstituted for Q includes 3- to 8-membered heterocyclic groupscontaining 1 to 5 hetero-atoms selected from oxygen, sulfur andnitrogen, and fused heterocyclic groups thereof, such as 2- or3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-,4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1-,2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or5-isothiazolyl, 3- or 5-(1,2,4-oxadiazolyl), 2- or5-(1,3,4-oxadiazolyl), 3- or 5-(1,2,4-thiadiazolyl), 2- or5-(1,3,4-thiadiazolyl), 4- or 5-(1,2,3-thiadiazolyl), 3- or4-(1,2,5-thiadiazolyl), 1-, 4- or 5-(1,2,3-triazolyl), 1-, 3- or5-(1,2,4-triazolyl), 1- or 5-(1H-tetrazolyl), 2- or 5-(2H-tetrazolyl),N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2-, 4- or5-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3- or4-pyridazinyl, indolyl, benzofuryl, benzothiazolyl, benzoxazolyl,triazinyl, oxotriazinyl, imidazo[1,2-a]pyridinyl,tetrazolo[1,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl, oxoimidazinyl,dioxotriazinyl, chromanyl, benzoimidazolyl, quinolyl, isoquinolyl,cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl,quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl,carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl,piperidinyl, piperidino, pyranyl, thiopyranyl, 1,4-dioxanyl,morpholinyl, morpholino, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl andpiperazino.

Each of the above-mentioned hydrocarbon groups and heterocyclic groupsmay have the same or different 1 to 5 substituents, preferably 1 to 3substituents, in substitutable positions. Moreover, in regard ofhalogen, each hydrocarbon or heterocyclic group may optionally besubstituted with up to the maximum possible number of halogen atoms. Thepreferred substituent includes C₁₋₁₅ alkyl groups such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl andpentadecyl, C₃₋₁₀ cycloalkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, C₂₋₁₀ alkenyl groups such as vinyl, allyl,2-methylallyl, 2-butenyl, 3-butenyl and 3-octenyl, C₂₋₁₀ alkynyl groupssuch as ethynyl, 2-propynyl and 3-hexynyl, C₃₋₁₀ cycloalkenyl groupssuch as cyclopropenyl, cyclopentenyl and cyclohexenyl, C₆₋₁₀ aryl groupssuch as phenyl and naphthyl, C₇₋₁₁ aralkyl groups such as benzyl andphenylethyl, nitro, nitroso, hydroxyl, mercapto, cyano, oxo, thioxo,carbamoyl, mono- or di-C₁₋₆ alkyl-carbamoyl groups such asmethylcarbamoyl and dimethylcarbamoyl, C₆₋₁₄ aryl-carbamoyl groups suchas phenylcarbamoyl, carboxyl, C₁₋₄ alkoxy-carbonyl groups such asmethoxycarbonyl and ethoxycarbonyl, C₆₋₁₄ aryloxy-carbonyl such asphenoxycarbonyl, sulfo, halogen such as fluorine, chlorine, bromine andiodine, C₁₋₄ alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, s-butoxy and t-butoxy, C₆₋₁₀ aryloxy groups such asphenoxy, C₁₋₄ alkylthio groups such as methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio andt-butylthio, C₆₋₁₀ arylthio groups such as phenylthio, C₁₋₄alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl,propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl,s-butylsulfinyl and t-butylsulfinyl, C₆₋₁₀ arylsulfinyl groups such asphenylsulfinyl, C₁₋₄ alkylsulfonyl groups such as methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,isobutylsulfonyl, s-butylsulfony and t-butylsulfonyl, C₆₋₁₀ arylsulfonylgroups such as phenylsulfonyl, C₁₋₄ alkoxysulfonyl groups such asmethoxysulfonyl, ethoxysulfonyl, propoxysulfonyl, isopropoxysulfonyl,butoxysulfonyl, isobutyloxysulfonyl, s-butoxysulfonyl andt-butoxysulfonyl, C₆₋₁₀ aryloxysulfonyl groups such as phenoxysulfonyl,amino, C₁₋₁₁ carboxylic acylamino groups such as acetylamino,propionylamino and benzoylamino, mono- or di-C₁₋₄ alkylamino groups suchas methylamino, ethylamino, propylamino, isopropylamino, butylamino,dimethylamino and diethylamino, C₃₋₆ cycloalkylamino groups such ascyclohexylamino, C₆₋₁₀ arylamino groups such as anilino, tri-substitutedsilyl groups such as trimethylsilyl, t-butyldimethylsilyl,triphenylsilyl and t-butylmethoxyphenylsilyl, C₁₋₁₁ carboxylic acylgroups such as formyl, acetyl and benzoyl, 3- to 6-membered heterocyclicgroups containing 1 to 5 hetero-atoms selected from oxygen, sulfur andnitrogen, and fused heterocyclic groups thereof, such as 2- or3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-,4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1-,2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or5-isothiazolyl, 1,2,3- or 1,2,4-triazolyl, 2-, 4- or 5-pyrimidinyl,benzothiazolyl, benzoxazolyl, triazinyl, oxiranyl, aziridinyl,pyrrolidinyl, piperidinyl, morpholinyl, benzimidazolyl, quinolyl andisoquinolyl. When two or more substituents are present, two of thesubstituents may form a divalent group such as C₁₋₆ alkylene (e.g.methylene, ethylene, trimethylene, tetramethylene and propenylene),3-oxapentamethylene, vinylene, benzylidene, methylenedioxy,2-thiatrimethylene, oxalyl, malonvl, succinyl, maleoyl, phthaloyl,oxygen, sulfur, imino, azo or hydrazo. When any of these substituents isaryl, aralkyl, cycloalkyl, cycloalkenyl aryloxy, arylthio, arylsulfinyl,arylsulfonyl, arylcarbamoyl, aryloxycarbonyl, aryloxysulfonyl,arylamino, cycloalkylamino, carboxylic acyl, carboxylic acylamino,tri-substituted silyl, heterocyclic group or divalent group, it mayfurther have 1 to 5 substituents such as halogen (e.g. fluorine,chlorine, bromine or iodine), hydroxyl, nitro, cyano, C₁₋₄ alkyl (e.g.methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl),C₂₋₄ alkenyl (e.g. vinyl or allyl), C₂₋₄ alkynyl (e.g. ethynyl or2-propynyl), phenyl, C₁₋₄ alkoxy (e.g. methoxy or ethoxy), phenoxy, C₁₋₄alkylthio (e.g. methylthio or ethylthio) and phenylthio, andparticularly in regard of halogen, the above-mentioned substituent mayoptionally be substituted with up to the maximum possible number ofhalogen atoms. When any of these substituents is alkyl, alkenyl,alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylcarbamoyl, alkoxycarbonyl, alkoxysulfonyl, amino or alkylamino, itmay further have 1 to 5 substituents such as halogen mentioned above,hydroxyl, nitro, cyano, C₁₋₄ alkoxy and C₁₋₄ alkylthio, and particularlyin regard of halogen, the above-mentioned substituent may optionally besubstituted with the maximum possible number of halogen atoms.

The electron attracting group for X includes nitro, cyano, C₁₋₁₀carboxylic acyl which may optionally be substituted with 1 to 5 halogenatoms (e.g. fluorine, chlorine, bromine or iodine) such as acetyl,trichloroacetyl, trifluoroacetyl, pentafluoropropionyl or benzoyl, 3- to6-membered heterocyclic-carbonyl containing 1 to 4 hetero-atoms selectedfrom oxygen, sulfur and nitrogen as ring-constituent atoms such asnicotinoyl, furoyl or thenoyl, carboxyl, C₁₋₄ alkoxycarbonyl such asmethoxycarbonyl or ethoxycarbonyl, C₆₋₁₀ aryloxy-carbonyl such asphenoxycarbonyl, 3- to 6-membered heterocyclic-oxycarbonyl containing 1to 4 hetero-atoms selected from oxygen, sulfur and nitrogen asring-constituent atoms such as pyridyloxycarbonyl or thienyloxycarbonyl,carbamoyl, C₁₋₄ alkylsulfonylthiocarbamoyl such asmethylsulfonyl-thiocarbamoyl, C₁₋₄ alkylsulfonyl which may optionally besubstituted with 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromineor iodine) such as methylsulfonyl, ethylsulfonyl ortrifluoromethylsulfonyl, sulfamoyl and C₁₋₄ dialkoxyphosphoryl such asdiethoxyphosphoryl.

The divalent hydrocarbon group of the divalent hydrocarbon group whichmay optionally be substituted for A includes C₂₋₄ alkylene such asethylene, propylene or trimethylene, C₁₋₄ alkenylene such as vinylene orpropenylene, C₃₋₁₀ cycloalkylene such as 1,2-cyclopentylene or1,2-cyclohexylene, C₃₋₁₀ cycloalkenylene such as1-cyclopropen-1,2-ylene, 1-cyclohexen-1,2-ylene or4-cyclohexen-1,2-ylene, and C₆₋₁₀ arylene such as O-phenylene. Thesubstituents of this divalent hydrocarbon group may for example be thosementioned as substituents of the hydrocarbon group which may optionallybe substituted for R¹.

The leaving group for Y¹ and Y² includes halogen (e.g. fluorine,chlorine, bromine, or iodine), C₁₋₄ alkylsulfonyloxy which mayoptionally be substituted with 1 to 3 halogen atoms (e.g. fluorine,chlorine, bromine or iodine) such as methanesulfonyloxy,ethanesulfonyloxy or trifluoromethanesulfonyloxy, C₆₋₁₀ arylsulfonyloxywhich may optionally be substituted with 1 to 4 substituents selectedfrom the group consisting of halogen (e.g. fluorine, chlorine, bromineor iodine) and C₁₋₄ alkyl (e.g. methyl, ethyl) such asbenzenesulfonyloxy, p-bromobenzenesulfonyloxy or mesitylenesulfonyloxy,C₁₋₆ carboxylic acyloxy which may optionally be substituted with 1 to 3halogen atoms (e.g. fluorine, chlorine, bromine or iodine) such asacetyloxy or trifluoroacetyloxy, C₆₋₁₀ aryl-carbonyloxy (e.g.benzoyloxy), C₁₋₄ alkylthio (e.g. methylthio or ethylthio), C₆₋₁₀arylthio which may optionally be substituted with 1 to 5 halogen atoms(e.g. fluorine, chlorine, bromine or iodine) such as phenylthio orpentachlorophenylthio, and 3- to 6-membered heterocyclic-thio containing1 to 4 hetero-atoms selected from oxygen, sulfur and nitrogen asring-constituent atoms (e.g. 2-pyridylthio or 2-benzothiazolylthio).Furthermore, Y¹ and Y² may jointly represent an oxygen atom or a sulfuratom.

The amine compound mentioned above may for example be ammonia, a primaryamine or a secondary amine, which are represented by the formula:

    R.sup.4 R.sup.5 NH

wherein R⁴ and R⁵ are the same or different, H or a hydrocarbon groupwhich may optionally be substituted; or both R⁴ and R⁵ are combined withthe adjacent nitrogen atom to form a cyclic amino group.

The hydrocarbon group which may optionally be substituted for R⁴ and R⁵may for example be those mentioned as the hydrocarbon group which mayoptionally be substituted for R¹ and R² including substituents thereof.The cyclic amino group which R⁴ and R⁵ may form together with theadjacent nitrogen atom includes aziridino, azetidino, pyrrolidino,morpholino and thiomorpholino.

The amino group which may optionally be substituted for R³ includesamino, secondary amino, which are represented by the formula:

    R.sup.4 R.sup.5 N--

wherein R⁴ and R⁵ are as defined above.

R¹ is preferably a saturated or unsaturated aliphatic hydrocarbon groupand more preferably a C₁₋₁₅ alkyl group. Particularly preferred are C₁₋₃alkyl groups, methyl being most preferred.

R² is preferably H or a saturated or unsaturated aliphatic hydrocarbongroup. Particularly preferred are H and C₁₋₁₅ alkyl. Still morepreferred are H and C₁₋₄ alkyl, H being most preferred.

R³ is preferably a secondary amino group and more preferably a C₁₋₄alkylamino group. Methylamino is most preferred.

The amine compound is preferably a primary amine, more preferably a C₁₋₄alkylamine. Methylamine is most preferred.

A is preferably C₁₋₄ alkylene, C₂₋₄ alkenylene and C₆₋₁₄ arylene, morepreferably C₆₋₁₄ arylene. Particularly preferred are ethylene,trimethylene, vinylene and O-phenylene, O-phenylene being mostpreferred.

Q is preferably a 5 or 6-membered aromatic heterocyclic group containingat least one nitrogen or sulfur atom as a ring-constituent atom, whichmay optionally be halogenated. Particularly preferred are halogenatedpyridyl and halogenated thiazolyl. Specifically, 6-chloro-3-pyridyl and2-chloro-5-thiazolyl are most preferred.

n is preferably 1.

X is preferably nitro or cyano, nitro being particularly preferred.

Y¹ and Y² are preferably both halogen as mentioned above, morepreferably chlorine.

The salts of guanidine derivative [I], compound [II], compound [V],compound [VI] and amine compound mentioned above can be anyagrochemically acceptable salts, typically salts with various inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,phosphoric acid, sulfuric acid and perchloric acid, and salts withvarious organic acids such as formic acid, acetic acid, tartaric acid,malic acid, citric acid, oxalic acid, succinic acid, benzoic acid,picric acid, methanesulfonic acid and p-toluenesulfonic acid. When anyof said guanidine derivative [I], compounds [II], [V] and [VI] and aminecompound has an acidic group such as carboxyl, it may form a salt with abase. The base which can be used includes inorganic bases such assodium, potassium, lithium, calcium, magnesium and ammonia, and organicbases such as pyridine, collidine, dimethylamine, triethylamine andtriethanolamine.

When compound [III] or [IV] has a basic group such as amino, it may formsalts with inorganic and organic acids such as those mentioned justabove. Moreover, when compound [III] or [IV] has an acidic group such ascarboxyl, it may form salts with inorganic and organic bases such asthose mentioned just above.

The process of the present invention can be carried out under theconditions described hereinafter. In case the reaction product obtainedis a free compound, it can be converted into the salts such as thosementioned above and conversely in case the reaction product is a salt,it can be converted into a free compound, by the known procedure ineither case. Furthermore, when the starting compound may form a saltsuch as those mentioned above, it can be used not only in the free formbut also in the form of a salt. Therefore, the following descriptions ofstarting compounds and reaction products should be construed to coverboth the free compounds and salts (e.g. salts with the acids or basesmentioned for guanidine derivative [I]).

(A) Compound [II] is reacted with compound [III] to give compound [IV].##STR14## (In the above reaction schema, all symbols are as definedabove)

With respect to compound [II], compound [III] is used in a proportion ofabout 0.8 to 5 equivalents, preferably about 1 to 1.5 equivalents, butit can be used in large excess unless it is detrimental to the reaction.

This reaction can be carried out advantageously in the presence of abase. The base includes various inorganic bases such as alkali metalhydrogen carbonates (e.g. sodium hydrogen carbonate and potassiumhydrogen carbonate), alkali metal carbonates (e.g. sodium carbonate andpotassium carbonate), alkali metal hydroxides (e.g. sodium hydroxide,potassium hydroxide), alkaline earth metal hydroxides (e.g. calciumhydroxide), alkyllithium (e.g. butyllithium), aryllithium (e.g.phenyllithium), alkali metal amides (e.g. sodium amide and lithiumdiisopropylamide), alkali metal hydrides (e.g. sodium hydride andpotassium hydride), alkali metal alkoxides (e.g. sodium methoxide andsodium ethoxide), alkali metals (e.g. sodium metal and potassium metal),and various organic bases such as triethylamine, tributylamine,N,N-dimethylaniline, pyridine, picoline, lutidine, collidine,5-ethyl-2-methylpyridine, 4-(dimethylamino)pyridine and1,8-diazabicyclo[5.4.0]undecene-7 (hereinafter abbreviated as DBU). Theabove organic bases can be used as solvents as well. With respect tocompound [III], the base is used in a proportion of about 0.5 to 20equivalents, preferably about 1.8 to 4 equivalents.

While the reaction can be conducted in the absence of a solvent, it isusually carried out in a solvent which does not interfere with thereaction. The solvent includes aromatic hydrocarbons such as benzene,toluene and xylene, halogenated hydrocarbons such as dichloromethane,chloroform, 1,2-dichloroethane and carbon tetrachloride, saturatedhydrocarbons such as hexane, heptane and cyclohexane, ethers such asdiethyl ether, tetrahydrofuran (hereinafter abbreviated as THF) anddioxane, ketones such as acetone and methyl ethyl ketone, nitrites suchas acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide(hereinafter abbreviated as DMSO), acid amides such asN,N-dimethylformamide (hereinafter abbreviated as DMF) andN,N-dimethylacetamide, esters such as ethyl acetate and butyl acetate,alcohols such as methanol, ethanol, propanol and isopropyl alcohol, andwater. These solvents can be used independently or, where needed, as anappropriate mixture of two or more species, for example in a ratio ofabout 1:1 to 1:10 (by volume). Where the reaction system is nothomogeneous, the reaction may be conducted in the presence of a phasetransfer catalyst such as quaternary ammonium salts, (e.g.triethylbenzylammonium chloride, tri-n-octylmethylammonium chloride,trimethyldecylammonium chloride, tetramethylammonium bromide andcetylpyridinium bromide) and crown ethers.

The reaction temperature is usually in the range of about -20 to 250°C., preferably about -10 to 50° C. The reaction time is usually in therange of about 10 minutes to 50 hours, preferably about 10 minutes to 10hours.

In this reaction step, it is sometimes advantageous to add a loweralcohol having 1 to 4 carbon atoms such as methanol and ethanol afterthe reaction to decompose the residual compound [III] to thecorresponding ester compound, facilitating the work-up procedure andleading to an improved purity of compound [IV]. The particularlypreferred lower alcohol is methanol. The preferred proportion of suchlower alcohol is about 0.1 to 5.0 equivalents with respect to compound[III]. The preferred decomposition time is in the range of about 10minutes to 5 hours. The preferred decomposition temperature is in therange of about 0 to 50° C.

(B) Compound [IV] is reacted with compound [V] to give compound [VI].##STR15## (In the reaction schema, all symbols are as defined above)

With respect to compound [IV], compound [V] is used in a proportion ofabout 0.8 to 5 equivalents, preferably about 1 to 1.5 equivalents,although it can be used in large excess unless it is detrimental to thereaction.

While this reaction is usually conducted in the absence of a base, thereare cases in which the reaction proceeds more efficiently in thepresence of a base such as those mentioned for process (A).

This reaction is generally conducted in a solvent which does notadversely affect the reaction. The solvent includes the solventsmentioned for process (A). When the reaction system is not homogeneous,a phase transfer catalyst such as those mentioned for process (A) can beemployed.

The reaction temperature is usually in the range of about -20 to 200°C., preferably about -10 to 50° C. The reaction time is usually in therange of about 10 minutes to 50 hours, preferably about 10 minutes to 10hours.

In this reaction, a cyclic imide compound of the following formula[VII]: ##STR16## wherein A is as defined above, is formed as aby-product. In many cases this compound [VII] can be separated by meansof a known technique such as the method utilizing a difference insolubility in a solvent or column chromatography. An alternativeprocedure (1) applicable to certain cases comprises dissolving thereaction mixture in a basic aqueous medium and neutralizing the solutionwith an acid gradually for sequential precipitation of compound [VI] andcompound [VII]. A further alternative procedure (2) comprises stirringthe reaction mixture in a basic aqueous medium at about 0 to 50° C. forabout 0.5 to 5 hours to decompose compound [VII] to a hardlyprecipitatable substance (e.g. dicarboxylic acid monoamide) andneutralizing the system with an acid to precipitate compound [VI]. Thebase that can be used for these separation procedures typically includesthe bases mentioned for process (A) and the acid that can be usedtypically includes the acids mentioned for conversion of guanidinederivative [I] and other compounds to salts.

(C) Compound [II] is also reacted with compound [V] to give compound[VI]. ##STR17## (In the above reaction schema, all symbols are asdefined above)

With respect to compound [II], compound [V] is used in a proportion ofabout 0.2 to 5 equivalents, preferably about 0.7 to 1.5 equivalents, butit can be used in large excess unless it is detrimental to the reaction.

This reaction can be carried out efficiently in the range of about pH 5to pH 8. The reaction is preferably conducted in the presence of anacidic substance to be carried out in such range of pH. The acidicsubstance includes inorganic acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid,perchloric acid and nitric acid, and organic acids such as formic acid,acetic acid, tartaric acid, malic acid, citric acid, oxalic acid,succinic acid, benzoic acid, picric acid, methanesulfonic acid andp-toluenesulfonic acid. With respect to compound [II], the acidicsubstance is used in a proportion of about 0.5 to 10 equivalents andpreferably about 0.1 to 2 equivalents.

While the reaction can be conducted in the absence of a solvent, it isusually carried out in a solvent such as those mentioned for process(A). When the reaction system is not homogeneous, a phase transfercatalyst such as those mentioned for process (A) can be employed.

Compound [VI] can be produced in particularly good yield by conductingthe above reaction either in water or in a mixture of water and anorganic solvent such as those mentioned above. In some instances, theyield can be further increased by adding a salt to the reaction system.The salt includes salts of the acids mentioned above with an alkalimetal (e.g. sodium and potassium), an alkaline earth metal (e.g.magnesium and calcium), a metal (e.g. copper, iron and zinc), orammonia. In certain instances, the reaction can be conducted in a buffersolution (e.g. phosphate buffer).

The reaction temperature is usually in the range of about -20 to 250°C., preferably about -10 to 50° C. The reaction time is usually in therange of about 10 minutes to 50 hours, preferably about 1 hour to 20hours.

(D) Compound [VI] is reacted with an amine compound to give guanidinederivative [I]. ##STR18## (In the above reaction schema, all symbols areas defined above)

The amine compound means the same compound as mentioned above.

With respect to compound [VI], the amine compound is used in aproportion of about 0.8 to 10 equivalents, preferably about 1 to 4equivalents but can be used in large excess unless it is detrimental tothe reaction.

In some cases, this reaction may proceed more efficiently in thepresence of a base such as those mentioned for process (A), but can beusually carried out without a base.

The reaction is usually carried out in a solvent such as those mentionedfor process (A). When the reaction system is not homogeneous, a phasetransfer catalyst such as those mentioned for process (A) can beemployed. The guanidine derivative [I] can be obtained in high yieldparticularly when the reaction is conducted in water or a mixture ofwater with an organic solvent such as those mentioned above. Theparticularly preferred organic solvent for use in such a solvent mixtureincludes said halogenated hydrocarbons such as dichloromethane,chloroform and 1,2-dichloroethane.

The reaction temperature is usually in the range of about -20 to 200°C., preferably about -10 to 50° C. The reaction time is usually in therange of about 10 minutes to 50 hours, preferably about 10 minutes to 10hours.

As for the starting compound [VI] for this reaction, the compound whichis synthesized by the above process (B) or (C) or any reaction analogoustherewith and then isolated can be used, but, the reaction mixturecontaining compound [VI] so synthesized can also be availabe. Thus, atypical procedure without isolating compound [VI] (1) comprisesconducting the above process (B) or (C) either in water or in a mixtureof water and an organic solvent (e.g. the organic solvents mentionedabove) and, then, adding the amine compound. An alternative procedure(2) comprises conducting the reaction according to the above process (B)or (C) in an organic solvent, adding water to the reaction mixture toprepare a binary phase, and adding the amine compound for reaction. Inthe latter procedure (2), the by-product compound [VII] may separate outafter the first-stage reaction and this by-product may be filtered offbut, of course, the process can be further continued without removingthe by-product.

The resulting compound [IV], compound [VI] and guanidine derivative [I],as well as their salts, can be respectively isolated and purified byknown procedures such as concentration, concentration under reducedpressure, distillation, fractional distillation, solvent extraction,change of pH, redistribution, chromatography, crystallization andrecrystallization.

Each of the guanidine derivative [I], compounds [II], [IV] and [VI], andtheir salts forms cis- and trans-isomers with respect to the position ofX and each of the guanidine derivative [I] and compounds [II] and [VI]may theoretically form tautomers depending on its substituent groups.All of these isomers are included in the corresponding guanidinederivative [I], compounds [II], [IV] and [VI], and their salts.

Some species of the compound [II] or a salt thereof which is used as astarting compound in the present invention are known compounds [cf. Rec.Trav. Chim., 81, 69 (1962) for instance]. When X represents nitro, thecompound [II] or a salt thereof can be produced by N-nitrating anisourea derivative [VIII] or a salt thereof as shown in the followingreaction schema. ##STR19## (wherein R¹ is as defined above)

The commonest nitrating agent is 60 to 100% nitric acid. However, analkali metal nitrate such as sodium nitrate and potassium nitrate, analkyl nitrate such as ethyl nitrate and amyl nitrate, nitroniumtetrafluoroborate (NO₂ BF₄), nitronium trifluoromethanesulfonate (NO₂CF₃ SO₃), or the like can be employed. With respect to compound [VIII],the nitrating agent can be used in a proportion of about 1.0 to 20equivalents and, taking nitric acid as an example, the preferredproportion is about 1.5 to 10 equivalents.

This reaction can be conducted in the absence of a solvent but isgenerally carried out in a solvent such as sulfuric acid, acetic acid,acetic anhydride, trifluoroacetic anhydride and trifluoromethanesulfonicacid. In certain cases, the solvents mentioned for process (A) or amixture thereof can be employed. The particularly preferred solvent issulfuric acid.

The reaction temperature is usually in the range of about -50 to 100°C., preferably about -20 to 30° C. The reaction time is usually in therange of about 10 minutes to 10 hours, preferably about 30 minutes to 3hours.

Compound [III] is commercially available or it can be produced byprocesses known per se or any reactions analogous therewith. Typicalprocesses are described in The Chemistry of Acid Derivatives, Part 1,John Willey & Sons (1979), Chapter 7; The Chemistry of Acid Derivatives,Part 2, John Willey & Sons (1979), Chapter 11; and The Chemistry ofAcylHalides, John Willey & Sons (1972), Chapter 2.

Compound [V] or a salt thereof can be produced by processes known per seor any reactions analogous therewith. Typical such processes aredescribed in Organic Functional Group Preparations, Academic Press, vol.1, Chapter 13 (1968); ditto, vol. 3, Chapter 10 (1972); and Japaneselaid-open Patent Application No. H 2-171. After produced, compound [V]or a salt thereof can be used as a reaction mixture without isolation inthe next process.

The amine compound or a salt thereof is commercially available, or itcan be produced by processes known per se or any processes analogoustherewith. Typical such processes are described in Survey of OrganicSyntheses, Wiley-Interscience (1970), Chapter 8.

The guanidine derivative [I] or a salt thereof as produced by theproduction technology of the present invention has an excellentpesticidal activity as disclosed in Japanese Patent Application Kokai H3-157308 and can be put to use in pesticidal compositions.

BEST MODE FOR CARRYING OUT OF THE INVENTION

The present invention is illustrated in further detail in the followingexamples, which do not limit the scope of the invention.

Proton NMR spectra were recorded with a Bruker AC-200P spectrometerusing tetramethylsilane as an internal standard and all δ values wereexpressed in ppm. The pH value was measured using pH-test paper unlessotherwise specified.

The abbreviations used in the following reference and working exampleshave the following meanings.

s: singlet, br: broad, d: doublet, t: triplet, m: multiplet, dd: doubletof doublets, J: coupling constant, Hz: Hertz, %: weight percent, m.p.:melting point, room temperature: ca 15-25° C.

REFERENCE EXAMPLE 1

To a mixture of O-methylisourea sulfate (5.00 g, 29.0 mmol) and 97%sulfuric acid (15.2 ml, 10 equivalents) was added 61% nitric acid (15.2ml, 7 equivalents) dropwise at room temperature over 10 minutes. Afterone hour of stirring, the reaction mixture was poured on ice (100 g),neutralized with 40% aqueous sodium hydroxide solution, and extractedwith ethyl acetate (300 ml). The extract was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to provide2.80 g (82.4% yield) of O-methyl-N-nitroisourea.

¹ H-NMR (DMSO-d₆): 3.76 (3H, s), 8.60-9.20 (2H, br. s).

M.p. 107-109° C.

REFERENCE EXAMPLES 2 TO 5

The reaction procedure of Reference Example 1 was repeated under theconditions described below to provide O-methyl-N-nitroisourea.

                  TABLE 1                                                         ______________________________________                                        Ref-                        Mol    Mol                                          erence Salt of Concentration equivalent equivalent                            Exam- O-methyl- of nitric of nitric of sulfuric Yield                         ple isourea acid (%) acid acid (%)                                          ______________________________________                                        1     Sulfate    61         7      10     82.4                                  2 Sulfate 67.5 7 10 88.2                                                      3 Sulfate 98 3 5 91.2                                                         4 1/2 Sulfate 98 3 9 89.6                                                     5 Hydrochloride 98 3 5 90.9                                                 ______________________________________                                    

REFERENCE EXAMPLE 6

To a mixture of O-methylisourea sulfate (1031 g, 5.99 mol) and 97%sulfuric acid (940 ml, 3 equivalents) was added 98% nitric acid (760 ml,3 equivalents) dropwise under ice-cooling over 2 hours. After 2 hours ofstirring at room temperature, the reaction mixture was poured on ice(5000 g). The mixture was then cooled to -15° C. and allowed to standfor 0.5 hour at this temperature and the resulting crystals werecollected by filtration. The crystals were suspended in water (1000 ml)and the suspension was adjusted to pH 8 with 40% aqueous sodiumhydroxide solution (160 ml) and stirred at room temperature for 0.5hour. The mixture was further stirred under ice-cooling for 0.5 hour andthe resulting crystals were collected by filtration and dried. As aresult, 542.7 g (76.1% yield) of O-methyl-N-nitroisourea was obtained.

REFERENCE EXAMPLE 7

To a mixture of O-methylisourea 1/2 sulfate (60.0 g, 0.49 mol) and 98%sulfuric acid (176.5 g, 1.76 mol) was added 98% fuming nitric acid (54.5g, 0.85 mol, 1.7 equivalents) dropwise over 1 hour at 4-8° C. After 2.5hours of srirring at 25° C., the reaction mixture was added to a mixtureof ice (400 g) and water (440 ml). The mixture was then cooled to -12°C. and allowed to stand for 1.5 hours at this temperature and theresulting crystals were collected by filtration. The crystals weresuspended in water (168 ml) and the suspension was adjusted to pH 8 with30% aqueous sodium hydroxide solution (8.0 g) and stirred at 10° C. for1 hour. The resulting crystals were collected by filtration and dried toprovide 38.4 g (66.2% yield) of O-methyl-N-nitroisourea.

EXAMPLE 1

In dichloromethane (460 ml)--pyridine (92 g, 1.16 mol) was dissolvedO-methyl-N-nitroisourea (46.2 g, 0.388 mol). This solution was cooled to-15° C. using an ice-methanol bath and phthaloyl chloride (95.0 g, 0.468mol) was added dropwise over 10 minutes. After 2 hours of stirring,methanol (12.5 g) was added and the mixture was further stirred for 15minutes. This reaction mixture was added to a mixture of concentratedhydrochloric acid (80 ml) and ice-water (400 ml), and the organic layerwas taken and concentrated under reduced pressure. The crude productthus obtained was added to 200 ml of methanol and the mixture wasstirred at room temperature for 30 minutes and under ice-cooling for 30minutes. The resulting crystals were collected by filtration to provide71.8 g (74.3% yield) of O-methyl-N-nitro-N'-phthaloylisourea.

¹ H-NMR (CDCl₃): 4.15 (3H, s), 7.80-8.15 (4H, m).

m.p. 137-138.5° C.

EXAMPLE 2

In methanol (10 ml) was suspended O-methyl-N-nitro-N'-phthaloylisourea(2.00 g, 8.03 mmol) and, then, 5-(aminomethyl)-2-chlorothiazole (1.20 g,8.07 mmol) was added dropwise over 15 minutes at 0° C. After 30 minutesof stirring at room temperature, the reaction mixture was diluted withwater (20 ml) under ice-cooling and the resulting crystals werecollected by filtration and dissolved in 10% aqueous sodium hydroxidesolution (10 ml). This solution was stirred for 30 minutes and thenadjusted to pH 4 with hydrochloric acid. The resulting crystals werecollected by filtration and dried to provide 1.70 g (85.0% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

¹ H-NMR (DMSO-d₆): 3.87 (3H, s), 4.61 (2H, d, J=5.5 Hz), 7.61 (1H, s),9.90 (1H, br. t, J=5.5 Hz).

m.p. 133-135° C.

EXAMPLE 3

Except that acetone was used as the reaction solvent, the reactionprocedure of Example 2 was otherwise repeated to provide the objectcompound in a yield of 74.0%.

EXAMPLE 4

Except that acetonitrile was used as the reaction solvent, the reactionprocedure of Example 2 was otherwise repeated to provide the objectcompound in a yield of 78.0%.

EXAMPLE 5

To a suspension ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea (1.00 g, 4.00mmol) in water (10 ml) was added 40% aqueous solution of methylamine(0.77 g; 9.92 mmol) dropwise. The mixture was stirred at roomtemperature for 14 hours and the resulting crystals were collected byfiltration, washed with water (10 ml), and dried. As a result, 0.92 g(92.0% yield) of1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine was obtained.

EXAMPLE 6

To a mixture of O-methyl-N-nitro-N'-phthaloylisourea (4.57 g, 18.3 mmol)and methanol (54 ml) was added 5-(aminomethyl)-2-chlorothiazole (2.96 g,19.9 mmol) dropwise over 30 minutes under stirring at 3° C. After 1 hourof stirring at room temperature, the reaction mixture was poured in 50 gof iced water and the mixture was stirred for 10 minutes. The resultingcrystals were collected by filtration and washed with water. Thecrystals were dissolved in 10% aqueous sodium hydroxide solution (60 ml)and the solution was stirred at room temperature for 0.5 hour. Thissolution was washed with chloroform (100 ml), brought to pH 4 withconcentrated hydrochloric acid and the resulting crystals were collectedby filtration. The crystals were washed with water. While a mixture ofthe above crystals and water (40 ml) was stirred at room temperature,40% aqueous solution of methylamine (3.78 g, 48.8 mmol) was added. Themixture was stirred at room temperature for 1 hour and the resultingcrystals were collected by filtration, washed with water, and dried toprovide 2.56 g (56.0% yield) of1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine.

M.p. 173.5-176.5° C.

EXAMPLE 7

To a mixture of O-methyl-N-nitro-N'-phthaloylisourea (2.90 g, 11.6 mmol)and dichloromethane (30 ml) was added a solution of5-(aminomethyl)-2-chlorothiazole (1.90 g, 12.8 mmol) in dichloromethane(15 ml) dropwise over 25 minutes under constant stirring at 3° C. Themixture was further stirred at room temperature for 1 hour and theresulting crystals were separated by filtration and washed with 12 ml ofdichloromethane. To the filtrate and washes combined was added water (30ml) and while this mixture was stirred at room temperature, 40% aqueoussolution of methylamine (1.89 g, 24.3 mmol) was added over 5 minutes.After 1 hour of stirring at room temperature, the resulting crystalswere collected by filtration, washed with water, and dried to provide2.15 g (74.0% yield) of1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine.

EXAMPLE 8

To a mixture of O-methyl-N-nitro-N'-phthaloylisourea (2.89 g, 11.6 mmol)and water (20 ml) was added 5-(aminomethyl)-2-chlorothiazole (1.79 g,12.0 mmol) en bloc under constant stirring at 3° C. The dropping funnelwas washed with acetonitrile (1 ml) and the washes were added to thereaction mixture. After 2 hours of stirring at room temperature, 40%aqueous solution of methylamine (3.97 g, 5.11 mmol) was added and themixture was stirred at room temperature for 40 minutes. The resultingcrystals were collected by filtration and washed with water. The washedcrystals were then stirred in acetonitrile (10 ml) for 15 minutes andthen collected by filtration to provide 1.50 g (51.8% yield) of1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine.

EXAMPLE 9

To a mixture of O-methyl-N-nitro-N'-phthaloylisourea (4.70 g, 18.9 mmol)and dichloromethane (25 ml) was added a solution of5-(aminomethyl)-2-chlorothiazole (2.80 g, 18.9 mmol) in dichloromethane(2 ml) dropwise over 5 minutes under constant stirring at roomtemperature. After 30 minutes of stirring at room temperature, 75 ml ofwater was added to the reaction mixture and, then, 40% aqueous solutionof methylamine (6.49 g, 83.6 mmol) was added over 2 minutes. The mixturewas stirred at room temperature for 1.5 hours and the resulting crystalswere collected by filtration, washed with water, and dried. As a result,3.49 g (73.5% yield) of1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine was obtained.

EXAMPLE 10

In a mixture of dichloromethane (10 ml) and water (15 ml) was suspendedO-methyl-N-nitro-N'-phthaloylisourea (5.0 g, 19.46 mmol) and then,dichloromethane (5 ml) solution of 5-(aminomethyl)-2-chlorothiazole(3.25 g, 20.69 mmol, 1.06 equivalents) was added dropwise over 5 minutesunder stirring at 10° C. After 30 minutes of stirring at roomtemperature, the reaction mixture was diluted with water (60 ml) andthen, methylamine (6.7 ml, 77.84 mmol, 4.00 equivalents) was added.After 1.5 hours of stirring at room temperature, the resulting crystalswere collected by filtration, washed with water and subsequentlymethanol. The washed crystals were dried to provide 3.83 g (78.8% yield)of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine as whitecrystals.

EXAMPLE 11

In a mixture of dichloromethane (10 ml) and water (15 ml) was suspendedO-methyl-N-nitro-N'-phthaloylisourea (5.0 g, 20.0 mmol) and then,dichloromethane (5 ml) solution of 5-(aminomethyl)-2-chloropyridine (3.0g, 21.0 mmol, 1.05 equivalents) was added dropwise over 5 minutes understirring at 10° C. After 30 minutes of stirring at room temperature, thereaction mixture was diluted with water (60 ml) and then, methylamine(6.7 ml, 77.84 mmol, 4.0 equivalents) was added. After 1.5 hours ofstirring at room temperature, 30 ml of 20% aqueous sodium hydroxidesolution was added to separate a water phase from an organic phase. Thewater phase was washed with dichloromethane, neutralized withconcentrated hydrochloric acid, and adjusted to pH 3.0. The resultingcrystals were collected by filtration, washed with water andsubsequently methanol. The washed crystals were dried to provide 3.12 g(64.0% yield) of 1-(6-chloro-3-pyridylmethyl)-3-methyl-2-nitroguanidineas white crystals. M.p. 159-160° C.

¹ H-NMR (DMSO-d₆) δ: 2.85 (3H, d, J=4.4 Hz), 4.44 (2H, d, J=6.0 Hz),7.49 (1H, d, J=8.2 Hz), 7.80 (1H, dd, J=8.2 Hz, 2.6 Hz), 7.90 (1H, br),8.37 (1H, d, J=2.6 Hz), 9.10 (1H, br).

IR(nujol): 3300, 1620, 1570, 1380, 1341, 1240 (cm⁻¹).

EXAMPLE 12

To a suspension ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea (87% purity,47.2 g, 0.164 mol) in water (410 ml) was added 40% aqueous solution ofmethylamine (25.5 g, 0.328 mol, 2.0 equivalents) dropwise at 23° C.After 2 hours of stirring at room temperature, the mixture was allowedto stand under ice-cooling and then, 36% hydrochloric acid (14.3 mol,0.168 mol) was added dropwise at 13-20° C. The resulting crystals werecollected by filtration to provide 39.1 g (95.6% yield) of1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine.

EXAMPLE 13

To a mixture of O-methyl-N-nitroisourea (3.0 g, 0.0252 mol), 36%hydrochloric acid (2.2 ml), and water (50 ml) was added5-aminomethyl-2-chlorothiazole (93% purity, 4.4 g, 0.0275 mol) at 20° C.This mixture was stirred at room temperature for 6 hours and thenextracted with dichloromethane. The extract was dried over anhydrousmagnesium sulfate and concentrated to provide 3.5 g (55.4% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

¹ H-NMR (DMSO-d₆): 3.87 (3H, s), 4.61 (2H, d, J=5.5 Hz), 7.61 (1H, s),9.90 (1H, br. t, J=5.5 Hz).

EXAMPLE 14

To a mixture of O-methyl-N-nitroisourea (2.0 g, 0.0168 mol), 36%hydrochloric acid (1.5 ml), sodium chloride (8.0 g), and water (40 ml)was added 5-aminomethyl-2-chlorothiazole (2.5 g, 0.0168 mol) at 20° C.This mixture was adjusted to pH 7 with 30% aqueous solution of sodiumhydroxide and stirred at room temperature for 8 hours, after which itwas extracted with dichloromethane. The extract was dried over anhydrousmagnesium sulfate and concentrated to provide 2.7 g (64.1% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

M.p. 133-135° C.

EXAMPLE 15

To a mixture of O-methyl-N-nitroisourea (2.0 g, 0.0168 mol), 36%hydrochloric acid (1.5 ml), sodium chloride (8.0 g), and water (40 ml)was added 5-aminomethyl-2-chlorothiazole (2.5 g, 0.0168 mol) at 20° C.This mixture was adjusted to pH 7 with 30% aqueous solution of sodiumhydroxide and stirred at room temperature for 13 hours. Then, 40%aqueous solution of methylamine (4.4 ml, 0.0511 mol) was added and themixture was stirred at room temperature for 2 hours. The resultingcrystals were collected by filtration, washed with water, and dried toprovide 1.54 g (36.7% yield) of1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine.

EXAMPLE 16

O-methyl-N-nitroisourea (3.0 g, 0.0252 mol), acetic acid (1.5 ml, 0.0262mol, 10.4 equivalents), and 5-(aminomethyl)-2-chlorothiazole (93%purity, 4.4 g, 0.0275 mol, 1.09 equivalents) were added to water (55 ml)in this order at 24° C. The reaction mixture was adjusted to pH 7 with30% aqueous sodium hydroxide solution. The mixture was stirred at roomtemperature for 2 hours and then extracted with dichloromethane. Theextract was dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to provide 2.9 g (46.0% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 17

Except that 67.5% nitric acid (1.7 ml, 0.0257 mol, 1.02 equivalents) wasused instead of acetic acid, the reaction procedure of Example 16 wasrepeated to provide 3.4 g (54.0% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 18

Except that 97% sulfuric acid (0.7 ml, 0.0127 mol, 0.5 equivalents) wasused instead of acetic acid, the reaction procedure of Example 16 wasrepeated to provide 2.9 g (46.0% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 19

O-methyl-N-nitroisourea (1.2 g, 0.01 mol) was added to water (30 ml)dissolving sodium chloride (4.7 g). Then, 70% perchloric acid (1.52 g,0.0106 mol, 1.06 equivalents) was added, and5-(aminomethyl)-2-chlorothiazole (1.49 g, 0.01 mol, 1.00 equivalent) wasadded at 24° C. The mixture was adjusted to pH 7 with 30% aqueous sodiumhydroxide solution. After 24 hours of stirring at room temperature, theresulting crystals were collected by filtration to provide 1.56 g (62.2%yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 20

5-(Aminomethyl)-2-chlorothiazole (7.43 g, 50.0 mmol) was dissolved inwater (96 ml), and 47% hydrobromic acid (5.78 ml 50.0 mmol) was added.The pH was 3.4 at this time. To this reaction mixture was addedO-methyl-N-nitroisourea (7.19 g, 60.0 mmol) and sodium chloride (17.5 g,0.30 mol), and adjusted to pH 6.2 with aqueous sodium hydroxide solution(0.5 N) using pH meter. After 24 hours of stirring at room temperature,the resulting white crystals were collected by filtration under reducedpressure, and washed with water. The washed crystals were dried underreduced pressure (80° C., 2 hours) to provide 8.7 g (69.4% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 21

O-methyl-N-nitroisourea (2.0 g, 0.0168 mol) was added to water (40 ml)dissolving calcium chloride dihydrate (8.0 g). Then, 36% hydrochloricacid (1.5 ml, 0.0176 mol, 1.05 equivalents) was added, and5-(aminomethyl)-2-chlorothiazole (2.5 g, 0.0168 mol, 1.00 equivalent)was added at 24° C. The mixture was adjusted to pH 7 with 30% aqueoussodium hydroxide solution. After 19 hours of stirring at roomtemperature, the resulting crystals were collected by filtration toprovide 2.48 g (59.1% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 22

To an aqueous solution (40 ml) of sodium chloride (7.9 g, 0.13 mol) wereadded O-methyl-N-nitroisourea (2.3 g, 19.3 mmol), concentratedhydrochloric acid (1.49 ml, 16.8 mmol) and5-(aminomethyl)-2-chlorothiazole (2.5 g, 16.8 mmol). The mixture wasadjusted to pH 7.0 with 30% aqueous sodium hydroxide solution, andstirred at room temperature for 3 days. The resulting white crystalswere collected by filtration under reduced pressure, and washed withwater. The washed crystals were dried under reduced pressure (80° C., 2hours) to provide 3.23 g (76.6% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 23

5-(Aminomethyl)-2-chlorothiazole (7.43 g, 50.0 mmol) was dissolved inwater (96 ml), and concentrated hydrochloric acid (4.22 ml, 50.0 mmol)was added. To this reaction mixture was added O-methyl-N-nitroisourea(7.19 g, 60.0 mmol), and adjusted to pH 6.7 with aqueous sodiumhydroxide solution (0.5 N) using PH meter. After 20 hours of stirring atroom temperature, maintaining pH 6.7, the resulting white crystals werecollecte by filtration under reduced pressure, and washed with water.The washed crystals were dried under reduced pressure (80° C., 2 hours)to provide 7.85 g, (62.6% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 24

5-(Aminomethyl)-2-chlorothiazole (1.49 g, 10.0 mmol) was dissolved indiluted hydrochloric acid (15 ml, 10.0 mmol), andO-methyl-N-nitroisourea (1.31 g, 11.0 mmol) was added. The pH was 2.1 atthis time. This reaction mixture was adjusted to pH 6.2 with aqueoussodium hydroxide solution (0.1 N, 4 ml, 0.40 mmol) using pH meter. Water(1 ml) was added to increase the whole volume to 20 ml. After 16 hoursof stirring at room temperature (pH was 7.1 at this time), the resultingwhite crystals were collected by filtration under reduced pressure, andwashed with water. The washed crystals were dried under reduced pressure(80° C., 2 hours) to provide 1.62 g (64.6% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 25

5-(Aminomethyl)-2-chlorothiazole (1.49 g, 10.0 mmol) was dissolved indiluted hydrochloric acid (15 ml, 10.0 mmol), andO-methyl-N-nitroisourea (1.31 g, 11.0 mmol) and sodium chloride (1.17 g,20.0 mmol) were added. pH was 2.1 at this time. This reaction mixturewas adjusted to pH 6.2 with aqueous sodium hydroxide solution (0.1 N,3.8 ml, 0.38 mmol) using pH meter. Water (1.2 ml) was added to increasethe whole volume to 20 ml. After 16 hours of stirring at roomtemperature (pH was 6.8 at this time), the resulting white crystals werecollected by filtration under reduced pressure, and washed with water.The washed crystals were dried under reduced pressure (80° C., 2 hours)to provide 1.72 g (68.6% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 26

5-(Aminomethyl)-2-chlorothiazole (1.49 g, 10.0 mmol), was dissolved indiluted hydrochloric acid (15 ml, 10.0 mmol), andO-methyl-N-nitroisourea (1.31 g, 11.0 mmol) and sodium chloride (4.68 g,80.0 mmol) were added. The pH was 1.9 at this time. This reactionmixture was adjusted to pH 6.2 with aqueous sodium hydroxide solution(0.1 N, 5.0 ml, 0.50 mmol) using pH meter. After 16 hours of stirring atroom temperature (pH was 6.7 at this time), the resulting white crystalswere collected by filtration under reduced pressure, and washed withwater. The washed crystals were dried under reduced pressure (80° C., 2hours) to provide 1.74 g (69.4% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 27

5-(Aminomethyl)-2-chlorothiazole (7.43 g, 50.0 mmol) was dissolved inwater (96 ml), and concentrated hydrochloric acid (4.22 ml, 50.0 mmol)was added. To this reaction mixture was added O-methyl-N-nitroisourea(6.25 g, 52.5 mmol) and chloroform (30 ml), and adjusted to pH 6.7 withaqueous sodium hydroxide solution (0.5 N) using pH meter. After 24 hoursof stirring at room temperature, maintaining pH 6.7, the organic phasewas separated from the water phase. The water phase was extracted withchloroform (100 ml), and the combined organic phase was concentratedunder reduced. Water (50 ml) was added to the residue to stir for awhile. The resulting crystals were collected by filtration under reducedpressure, and washed with water. The washed crystals were dried underreduced pressure (80° C., 2 hours) to provide 7.80 g (62.2% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 28

To an aqueous solution (31 ml) of sodium chloride (6.1 g, 0.10 mol) andO-methyl-N-nitroisourea (1.5 g, 12.9 mmol) was added5-(aminomethyl)-2-chlorothiazole hydrochloride (2.4 g, 12.5 mmol). Thereaction mixture was adjusted to pH 7.0 with aqueous sodium hydroxidesolution, and stirred at room temperature for 4 hours. The resultingwhite crystals were collected by filtration under reduced pressure, andwashed with water. The washed crystals were dried under reduced pressure(80° C., 2 hours) to provide 1.92 g (60.8% yield) ofO-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.

EXAMPLE 29

To a mixture of O-methyl-N-nitroisourea (1.25 g, 10.53 mmol), water (20ml) and concentrated hydrochloric acid (0.85 ml, 10.03 mmol) was added5-(aminomethyl)-2-chloropyridine (1.43 g, 10.03 mmol) dropwise over 5minutes at room temperature with stirring. The reaction mixture wasneutralized with 40% aqueous sodium hydroxide solution and adjusted topH 7.2. After 17 hours of stirring at room temperature, the resultingcrystals were collected. The crystals were washed with water and dried.As a result, 1.16 g (47.3% yield) ofO-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea was obtained aswhite crystals. M.p. 112-113° C.

¹ H-NMR (CDCl₃) δ: 3.98 (3H, s), 4.57 (2H, d, J=6.0 Hz), 7.38 (1H, d,J=8.2 Hz), 7.63 (1H, dd, J=8.2 Hz, 2.4 Hz), 8.36 (1H, d, J=2.4 Hz), 9.43(1H, br). IR (nujol): 3250, 1590, 1520, 1390, 1240, 1210 (cm⁻¹).

EXAMPLE 30

To a mixture of O-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea(970 mg, 3.96 mmol) and water (30 ml) was added 40% aqueous solution ofmethylamine (0.7 ml, 7.92 mmol, 2.0 equivalents) at room temperaturewith stirring. After 1.5 hours of stirring at room temperature, theresulting crystals were collected. The crystals were washed with waterand methanol, and dried. As a result, 860 mg (89.1% yield) of1-(6-chloro-3-pyridylmethyl)-3-methyl-2-nitroguanidine.

Industrial Applicability

According to the production of the present invention using the compound[II] and/or the novel compound [IV], the guanidine derivative [I] or asalt thereof having excellent pesticidal activity can be producedadvantageously on a commercial scale.

We claim:
 1. A process for producing a compound of the forumula:##STR20## wherein R¹ is a hydrocarbon group which is substituted orunsubstituted, R² is H or a hydrocarbon group which is substituted orunsubstituted, Q is a heterocyclic group which is substituted orunsubstituted, X is an electron attracting group, and n is 0 or 1, or asalt thereof, which comprises(A) reacting a compound of the formula:##STR21## wherein the symbols are as defined above, or a salt thereof,with a compound of the formula:

    Q--(CH.sub.2).sub.n --NH--R.sup.2                          [V]

wherein the symbols are as defined above, or a salt thereof, or (B)reacting a compound of the formula (II) or a salt thereof, with acompound of the formula: ##STR22## wherein A is a divalent hydrocarbongroup which is substituted or unsubstituted, and Y¹ and Y² are the sameor different leaving group, and further reacting the resultant compoundof the formula: ##STR23## wherein the symbols are as defined above, withthe compound of the formula (V) or a salt thereof.
 2. A processaccording to claim 1, wherein R¹ is a C₁₋₃ alkyl group.
 3. A processaccording to claim 1, wherein X is nitro.
 4. A process according toclaim 1, wherein R² is H or a C₁₋₄ alkyl group.
 5. A process accordingto claim 1, wherein Q is a 5- or 6-membered aromatic heterocyclic group,having at least one nitrogen atom or sulfur atom, which is unhalogenatedor halogenated.
 6. A process according to claim 1, wherein n is
 1. 7. Aprocess according to claim 1, wherein the reaction in process (A) isperformed, and is conducted in water or in a mixture of water and anorganic solvent.
 8. A process according to claim 1, wherein the reactionin process (A) is performed, and is conducted in the range of about pH 5to pH
 8. 9. A process for producing the compound (VI) or a salt thereof##STR24## wherein R¹ is a hydrocarbon group which is substituted orunsubstituted, R² is H or a hydrocarbon group which is substituted orunsubstituted, Q is a heterocyclic group which is substituted orunsubstituted, X is an electron attracting group, and n is 0 or 1, whichcomprises reacting a compound (IV) ##STR25## wherein A is a divalenthydrocarbon group which is substituted or unsubstituted, with a compound(V)

    Q--(CH.sub.2).sub.n --NH--R.sup.2                          (V)

or a salt thereof.
 10. A process for producingO-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea or a salt thereof,which comprises reacting O-methyl-N-nitroisourea or a salt thereof with5-(aminomethyl)-2-chloropyridine or a salt thereof.
 11. A process forproducing O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea or asalt thereof, which comprises reacting O-methyl-N-nitroisourea or a saltthereof with 5-(aminomethyl)-2-chlorothiazole or a salt thereof.
 12. Aprocess according to claim 1, wherein method (A) is used.
 13. A processaccording to claim 1 wherein method (B) is used.